JP5584396B2 - Fluid path system for dissolution and transport of hyperpolarized materials - Google Patents

Description

  The present invention relates generally to methods and apparatus for lysing and transporting frozen formulations in fluid pathway systems used in magnetic resonance imaging (MRI) and analytical high resolution NMR spectroscopy.

  MRI is a diagnostic technique that has become particularly attractive to physicians because it is non-invasive and does not require exposing the patient under consideration to x-rays associated with other medical imaging techniques. Analytical high resolution NMR spectroscopy is regularly used in measuring molecular structure.

MRI and NMR spectroscopy, however, may be insensitive due to the normally very low polarization of commonly used contrast agent nuclear spins. Thus, there are several techniques for improving nuclear spin polarization in the solid phase. These techniques are known as hyperpolarization techniques and lead to increased sensitivity. In hyperpolarization techniques, a sample of contrast agent, such as ¹³ C1-pyruvate, or another similar polarized contrast agent is guided or ejected into the object to be imaged. As used herein, the term “polarization” refers to a change in the physical properties of a material for further use in MRI. Further, as used herein, the term “hyperpolarization” refers to being polarized at levels above those found at room temperature and 1 Tesla, and is described in US Pat. No. 6,466,814. Further described.

  In many instances, the contrast agent undergoes this hyperpolarization at a device away from its end use. Hyperpolarized materials have a very short lifetime, so that hyperpolarized materials must be quickly transported from their source to the intended end-use location (ie, infusion into the patient) and converted to a usable situation. Don't be. To accomplish this, the cryogenic frozen hyperpolarized material is dissolved in a dissolution medium for injection into the patient. Therefore, as part of a dynamic nuclear polarization (DNP) system, it must include a means to dissolve the polarized sample within the polariser.

  For samples of polarized acid (eg, pyruvate), it is necessary to use a dissolution medium to dissolve the sample and obtain a solution of polarized sodium salt (eg, sodium pyruvate) suitable for in vivo injection. The dissolution medium is usually an aqueous solution containing a base (eg, sodium hydroxide) and a buffer to dissolve / sample the physiologically acceptable pH in the infusate (eg, TRIS hydroxymethylaminomethane ( TRIS)), but the dissolution medium may also be in the form of water.

  In current methods, a defined amount of dissolution medium containing sodium hydroxide, TRIS-buffer, and EDTA is pressurized with helium gas to a defined pressure in a titanium cylinder and heated to a defined temperature. When the dissolution process begins, the pressurized and heated solvent is released from the cylinder and is guided by the continuous helium gas flow to contact the polarized sample. This method has the disadvantage that the dissolved sample is mixed with the gas as it is injected into the receiving container and is therefore not aseptic for injection. This complicates removal of the electron paramagnetic agent (EPA) from the dissolved polarized sample and aseptic filtration of the infusate.

  Additional problems can arise with existing methods that utilize fluid path systems to lyse frozen samples. That is, one possible failure mode in current fluid path systems needs to ensure that the sample is completely dissolved by the dissolution medium. If the heat energy, quantity and flow of the dissolution medium are not sufficient to completely dissolve the sample, the system will freeze before the sample is dissolved, so that the ice plug will enter and exit the fluid path system. May completely block the flow. The second failure mode is that the thermal energy delivered to the frozen sample is not sufficient to melt the entire sample, so that after a specified amount of dissolution medium has entered the fluid path system, a portion of the sample is frozen. / It leads to staying in a solid state. This inability to completely dissolve the sample affects the pH level and acid concentration of the infusate when the sample is acid. For example, pyruvate is a highly reactive compound that is sensitive to both high and low pH (which can be catalyzed to react pyruvate) and is therefore in the infusate. It is important to completely dissolve the sample to ensure the desired pH level.

Another limitation of current methods and equipment used to dissolve pharmaceutical samples is the cost and complexity associated with maintaining sterile products. In formulations, sterility assurance is fundamental and there is no risk of contamination of the product. Current methods and devices require handling and exposing the sample to the environment. In this way, any device that contacts the sample must be sterilized and sterility must be ensured during sample dissolution and transport.
US Pat. No. 6,466,814

  Accordingly, there is a need for a fluid pathway system that can rapidly and completely dissolve frozen hyperpolarized material. It is also desirable that the dissolved material be completely displaced from its initial position to its final position to ensure proper pH level, acid concentration, and liquid state polarization in the injectable solution. The fluid pathway system should also maintain sterility during material dissolution and transport in a cost-effective and efficient manner.

  The present invention overcomes the above disadvantages by providing an apparatus and method for lysing and transporting a frozen formulation in a fluid pathway system. The fluid pathway system performs rapid and complete dissolution of the frozen hyperpolarized material and removes the resulting hyperpolarized solution from its initial position in the polariser system for use (eg, for infusion into a patient). Transport to final position outside the polariser system.

  According to one aspect of the present invention, a fluid pathway system includes a vial with a frozen formulation therein, an output end in fluid communication with the vial and an input end attached to a pressure vessel containing a dissolution medium. And a delivery fluid path having a first end airtightly attached to the vial to transport a mixture of the dissolved formulation and dissolution medium therefrom. A fluid path system is also positioned between the holding container coupled to the second end of the transport fluid path to receive the mixture and the pressure container and the dissolution fluid path to control the flow of the dissolution medium. A dissolving fluid path valve and a conveying fluid path valve for controlling the flow of the mixture from the conveying fluid path to the holding vessel.

  According to another aspect of the present invention, a polariser system that polarizes a material used in magnetic resonance (MR) imaging creates a magnetic field and creates a magnetic field by cooling the material that is hyperpolarized to a cryogenic temperature. And a superconducting magnet positioned around the cryogenic cooling system for hyperpolarization. The polariser system also includes a fluid delivery system that dissolves and carries the hyperpolarized material. The fluid delivery system further comprises a sample container having a material to be hyperpolarized therein, a syringe having a dissolution medium therein, and an inner tube coupled to the syringe for receiving and transporting the dissolution medium therethrough. The inner tube is in fluid communication with a sample container having an internal volume in which the dissolution medium and the hyperpolarized material are in fluid contact. The fluid delivery system also includes an outer tube that is hermetically coupled to the sample container to carry the hyperpolarized solution from the sample container consisting of the dissolution medium and the dissolved hyperpolarized material.

  According to yet another aspect of the present invention, a method of manufacturing a fluid path system hermetically seals a first end of an outer tube against a vial containing a solid material that is hyperpolarized therein. And positioning the inner tube within the outer tube, the inner tube having an output end in fluid communication with the interior volume of the vial. The method also includes connecting a syringe having a dissolution medium therein to the input end of the inner tube and connecting a holding container to the second end of the outer tube to receive the hyperpolarized solution therein. The hyperpolarized solution comprises a dissolution medium and a dissolved hyperpolarized material.

  Various features and advantages of the present invention will become apparent from the following detailed description and drawings.

  The drawings illustrate embodiments presently contemplated for carrying out the invention.

Referring to FIG. 1, a fluid pathway system 10 (ie, a fluid delivery system) for lysing and transporting a frozen formulation is shown. In one embodiment, the frozen formulation is a sample 12 of solid hyperpolarized material that is used as a contrast agent in magnetic resonance imaging (MRI) and NMR spectroscopy. For example, sample 12 may consist of ¹³ C1-pyruvate, but other contrast agents are possible. The fluid pathway system 10 can be made of medical grade material when used in a clinical setting to condition and deliver an injectable solution to a patient. Such materials are known and are usually plastics of effective quality with respect to leachable and stability. The material of the fluid path system 10 is further selected based on its thermal, mechanical and chemical properties to be compatible with the product and environment (ultra-low and superheat temperatures and high pressure). The fluid pathway system 10 is designed to provide a sterility barrier to the sample and the resulting solution, and all assemblies and components therein are designed to prevent the barrier from being unintentionally broken by the user. Further, although the fluid pathway system 10 can be made as a disposable part (ie, a single use), it is believed that it can be fully or partially reused. A single use fluid path system ensures maximum sterility and patient safety.

The fluid path system 10 is integrated with a device 14 that hyperpolarizes the sample 12. The polarization device 14 is formed in part by a vacuum chamber 16 that surrounds the internal components of the device. Positioned in the vacuum chamber 16 is a system 18 that cryogenically cools a sample of ¹³ C1-pyruvate, which works together to hyperpolarize the sample 12, and a superconducting magnet 20. In the embodiment of FIG. 1, the cryogenic cooling system 18 includes a liquid helium bath 22 stored in a container 24 to form a chamber that is cooled to cryogenic temperatures. Sample 12 is immersed in liquid helium bath 22 and a magnetic field of approximately 3.5 Tesla is generated by superconducting magnet 20 to provide a condition for hyperpolarizing sample 12. Microwave irradiation at an appropriate frequency is performed by a microwave radiation source (not shown) to polarize the solid sample 12 by dynamic nuclear polarization (DNP).

  A portion of the fluid path system 10 extends downward into the vacuum chamber 16 of the polarization device 14. To maintain a vacuum within the vacuum chamber 16, a sliding seal 26 is positioned around that portion of the fluid path system 10 that forms a junction or interface in the vacuum chamber 16. The sliding seal 26 is configured to slide along the fluid path system 10 as needed while further forming an airtight seal with the vacuum chamber 16 and the container 24. Therefore, the desired vacuum state is maintained by the sliding seal 26 in the polarization device 14 that hyperpolarizes the sample 12. Also, an airlock / ante chamber (such as a bellows (not shown) attached to the outer tube 44) or through which the vial 28 can pass when entering the polarization device 14 and the liquid helium bath 22. It is contemplated that other means of ensuring a vacuum connection to chamber 16 and vessel 24 at a low leakage rate can be implemented.

  The sample 12 positioned in the polariser system 14 is a liquid medicine formed of the sample and other commonly used solvents or materials that do not react to the solution that can be used to dissolve the sample 12. It is contained in a bottle 28 (ie, a sample container). The vial 28 can be formed of glass or another suitable material that does not react with the sample 12 or dissolution medium. When the vial 28 is made of a conductive material, care must be taken in carrying the DNP and optionally microwaves for nuclear magnetic resonance (NMR) detection. A specific amount or dose of sample 12 is contained in the vial 28, mixed with the dissolution medium solution, and finally injected into the patient. Usually, this amount / dose of sample 12 is approximately 2 ml in volume, but the exact amount is measured by a recognized health agency. The vial 19 is dimensioned so that the amount of the sample 12 contained therein fills only a part of the internal volume 30 of the vial 28, and the frozen sample 12 is placed at the bottom of the vial 28. It is positioned. It is also conceivable to freeze the sample 12 in other positions in the vial 28, for example, by coating the wall of the vial, so as to form a hollow cylinder of the sample product.

  A vial 28 is included as part of the fluid path system 10 that extends downward into the vacuum chamber 16. In fact, fluid path system 10 is used to lyse cryogenic frozen sample 12 with an aqueous solution and transport the lysed sample from vacuum chamber 16 to the desired end location where it is injected into the patient. A pressure vessel 32 is included in the fluid path system 10 to provide an aqueous solution to dissolve the sample 12 within the vial 28. In one embodiment, the pressure vessel is a syringe 32 that may be in the form of a motorized or pneumatic syringe that generates a force to inject a dissolution medium 34 (ie, a buffer solution) into the fluid pathway system 10. . The dissolution medium 34 therein is in a superheated state that melts and dissolves the cryogenic frozen sample 12 when mixed with it. Depending on the configuration, dissolution medium 34 may be heated to a temperature of up to about 150 ° C. in a pressure chamber (not shown) or other suitable heating device. The dissolution medium 34 includes a basic solvent such as sodium hydroxide to neutralize pyruvic acid and possibly an ion chelator (eg, EDTA). The dissolution medium 34 also contains therein a buffer, usually in the form of a buffer salt such as TRIS, although other known buffer salts can be used. Although the dissolution medium 34 listed above is described as consisting of sodium hydroxide, EDTA, and TRIS, it is contemplated that water or other solutions could be used instead.

  A dissolved fluid path 36 (ie, an inner tube) is attached to the syringe 32 that forms a fluid path between the syringe 32 and the vial 28 containing the sample 12. The input end 38 of the inner tube 36 is sealed and connected to the syringe 32. A dissolved fluid pathway valve 40 disposed within the inner tube 36 is positioned near the input end 38 of the inner tube 36 and adjacent to the syringe 32. This inner tube valve 40 serves to control the fluid flow of the dissolution medium 34 from the syringe 32 into the inner tube 36, so as to dissolve the sample 12 and adjust the pH of the resulting hyperpolarized solution. An amount of dissolution medium 34 can be injected into the fluid path system 10. The output end 42 of the inner tube 36 extends downward into the internal volume 30 of the vial 28 and is therefore in fluid communication therewith. The inner tube 36 maintains a temperature in the dissolution medium 34 and has a low thermal conductivity so as to minimize the loss of heat energy therefrom as it passes down through the inner tube 36 in the vial 28. Preferably, it is made of a material having a rate. Indeed, the inner tube 36 carries the dissolution medium 34 downward from the syringe 32 into the vial 28 in a heated state. In the internal volume 30 of the liquid vial 28, the heated dissolution medium 34 comes into contact with the frozen sample 12. The dissolution medium 34 dissolves the entire sample 12 to form a mixture that forms a hyperpolarized solution. The resulting hyperpolarized solution is in the form of an intravenous solution that can be injected directly into the patient, as recognized by the recognized health authorities.

  A transport fluid path 44 (ie, outer tube) is also included in the fluid path system 10 to create a separate fluid path from the inner tube 36. In one embodiment, and as shown in FIG. 1, the inner tube 36 is positioned within the outer tube 44, but when both are connected to the vial 28, the side-by-side tubes 36 and 44 are side-by-side. It is also conceivable that other arrangements such as configurations can be implemented. The outer tube 44 is also made of a low conductivity material that is not only between the inner tube 36 and the outer tube 44 but also on the inner side to prevent heat transfer between the outer tube 44 and the ambient environment of the vacuum chamber 16. It is preferable to have a different thermal conductivity than the tube 36 and the low temperature present therein by the liquid helium bath 22. The first end 46 of the outer tube 44 is hermetically sealed to the vial 28 so as to form a fluid connection therebetween without leakage. As noted above, the hyperpolarized solution is formed from the dissolution medium 34 and the dissolved sample 12 and placed in the internal volume 30 of the vial 28. As more dissolution medium 34 is injected into the inner tube 36 and down into the vial 28 to dissolve the sample 12, the amount of hyperpolarized solution increases and is pushed out of the vial 28. It is. The hyperpolarized solution thus flows into the outer tube 44 and forms an outer fluid path for the transport of the hyperpolarized solution. The hyperpolarized solution flows through the outer tube 44 and gradually into a receiving vessel 55 (ie, flask) attached to the second end 50 of the outer tube 44, where it is collected until the desired amount of hyperpolarized solution is created. To do. The outer tube 44 can be integrally coupled to or separately fitted onto the flask 55 and can include a nozzle (not shown) at the second end 50 that enters the flask 55. .

  In order to regulate the flow of the hyperpolarized solution between the vial 28 and the flask 55, a transport fluid path valve 52 is disposed in the outer tube 44. In one embodiment, the outer tube valve 52 is positioned near the syringe 32. The outer tube valve 52 is disposable and can be replaced in the fluid pathway system 10 as needed. Also included in the outer tube 44 is a filter cartridge 54 that removes the electron paramagnetic agent (EPA) from the hyperpolarizing solution and possibly other processing agents that can be added to hyperpolarize the sample 12. The EPA filter cartridge 54 is suitable for removing and injecting EPA from the hyperpolarized solution. In addition, the EPA filter cartridge can act as a heat sink to cool the hyperpolarized solution to a lower temperature that is more appropriate for injecting the patient.

  After passing through the EPA filter cartridge 54, the hyperpolarized solution can optionally pass through the outer tube 44 and into the holding vessel 48 where it can be held for a short time to mix the solution, allowing automatic quality control inspection. Can be done as needed. In one embodiment, further cooling of the hyperpolarized solution can be achieved by reducing the pressure in and / or by diluting the solution with an amount of water for injection (eg, 10 ml) that is at room temperature. Can be done within. Water may already be present in the container 48 or can be added to it during the accumulation of the hyperpolarized solution. The pressure reduction, and the addition of water, provides the necessary further cooling to bring the temperature of the resulting hyperpolarized solution from about 80 ° C. to 50 ° C., but the temperature of the solution is determined by these methods at a temperature point appropriate for injection (eg, It is conceivable that the temperature can be further reduced to ˜38 ° C.).

  After mixing and cooling the hyperpolarized solution, the solution is pushed out of the holding vessel 48 and travels under the outer tube 44 to the receiving vessel 55 (ie, flask) prior to final injection into the patient. A heat exchanger is placed between the holding vessel 48 and the flask 55 in the outer tube so as to further cool the hyperpolarized solution (if necessary) to a temperature threshold set at 38 ° C. for injection of the solution into the patient. 44 can be connected. As noted above, the temperature of the hyperpolarized solution may be in the range of 50 ° C. when exiting the holding vessel 48. Because the hyperpolarized solution is in a hyperpolarized state for a short period of time (eg, about 1 minute), the heat exchanger 57 allows further cooling of the solution in a rapid and efficient manner. The heat exchanger 57, such as copper, allows the solution to pass through the heat exchanger 57 with a minimum period of time (ie, having a high flow capacity) while further removing a large amount of heat therefrom. Configured as part of a material with excellent thermal conductivity. Copper provides the desired heat transfer properties, but is not compatible with sterility or liquid state polarization. Thus, the copper surface in the heat exchanger 57 that contacts the hyperpolarized solution is gold plated to form a more sterile and non-reactive fluid pathway. To further meet the sterility requirements associated with injectable hyperpolarized solutions, heat exchanger 57 is also designed to be easily disassembled for cleaning, and all components and compartments within the heat exchanger Is accessible. In this manner, the heat exchanger 57 can be formed in two removable halves or in some other similar configuration to accommodate easy assembly and disassembly. It is also contemplated that the heat exchanger 57 is a single use disposable part with the rest of the fluid path system 10. The heat exchanger 57 is also free of terminations or other areas that may be trapped to minimize loss of solution as the hyperpolarized solution passes through it. As noted above, heat exchanger 57 may be optional, and inclusion in fluid pathway system 10 depends on the temperature of the dissolution medium in syringe 32 and the thermal mass of other components in the system.

  Upon exiting the heat exchanger 57, it is contemplated that the hyperpolarized solution can pass through the additional sterile filter 59 under the outer tube 44. A filter 59 can optionally be added to the fluid path system 10 to further ensure sterilization of the hyperpolarized solution, although the fluid path system 10 may be designed as a sterilization system without the filter 59. I understand. The filter 59 can be composed of a membrane and / or resin and is known in the art and can take the form of a filter as used for sterile filtration of intravenous solutions and injectable drugs. it can. After exiting filter 59, the solution then passes into flask 55. Additional dissolution medium or water for injection can be added to flask 55 (or flask) to mix with the hyperpolarized solution as necessary to create the desired temperature, concentration, and / or pH level. May already exist within). To ensure that the temperature, concentration, and pH of the hyperpolarized solution in flask 55 are then at a pH and concentration appropriate for infusion at or below the threshold temperature of 38 ° C. and to the patient, It can be measured by the operator.

  As described above, inclusion of heat exchanger 57 and filter 59 in fluid passage system 10 is optional. A holding vessel 48 is also optional, and the fluid path system 10 is designed to provide a hyperpolarized solution having a desired temperature directly to the receiving vessel / flask 55 or the function of the holding vessel 48 within the flask 55. It is conceivable that it can be implemented.

  A nozzle 56 is positioned at the output end 42 of the inner tube 36 and at least partially positioned in the vial 28 to assist dissolution of the sample 12 within the fluid path system 10. As shown in FIG. 2, the nozzle 56 is positioned in the vial 28 adjacent to the hyperpolarized sample 12 so that it directly contacts the sample 12 as the dissolution medium 34 exits the nozzle 56. The nozzle 56 is necessary to completely and efficiently dissolve the sample 12, and then the resulting hyperpolarized solution is pushed from the vial 28 into the outer tube 44 and gradually into the holding container 48 and the flask 55. Helps create fluid flow characteristics within the dissolution medium 34.

  Several factors regarding nozzle 56 configuration and placement affect the dissolution of the hyperpolarized sample 12. That is, the nozzle 56 can be designed to have a nozzle diameter 58 and depth 60 that creates the desired fluid flow characteristics for dissolution of the sample 12 and can be located at a selected distance 62 from the material 12. . In one embodiment, the nozzle diameter 58 is 0.9 mm and is contemplated to be attached to the inner tube 36 having an outer diameter of 1.83 mm. The inner tube 36 is positioned within an outer tube 44 that is hermetically sealed to the vial 28, and the outer tube 44 has an inner diameter of 2.69 mm. The nozzle 56 also has a depth 60 of 1-3 mm. The diameter measurement described above leads to a flow area ratio of about 1.6. Such a ratio, together with the nozzle depth selected above, dissolves the sample 12 and causes the dissolution medium 34 to push the mixture of dissolution medium and dissolved sample (ie, hyperpolarized solution) out of the vial 28. Leads to the desired fluid flow.

  Compared to the sample 12, the arrangement of the nozzle 56 also affects the dissolution efficiency. The distance 62 (ie, “standoff”) between the surface 64 of the frozen sample 12 and the nozzle 56 not only affects lysis efficiency, but the segment of the frozen sample 12 breaks the nozzle 56 and inner tube 36 and becomes clogged. It is important to ensure that the fluid flow in the fluid path system 10 is not blocked. That is, if the nozzle 56 is placed too close to the surface 64 of the sample 12, the sample 12 may melt and refreeze and block the nozzle 56 before the dissolution medium 34 is injected therethrough. In one embodiment, the standoff 62 is set to 5 mm and is combined with the nozzle dimensions. Such a combination of standoff measurement and nozzle dimensions provides one particular configuration in which dissolution of the hyperpolarized sample 12 is achieved in the desired manner. Although specific measurements were made at nozzle diameter 58 and depth 60 and on standoff 62 between nozzle 56 and sample surface 64, other suitable measurements and flow area ratios can also be made. Can be considered. The exact value (ie, measurement and distance) is determined when designing the fluid path system 10 is based on at least one of the values of the temperature of the dissolution medium 34, the pressure of the dissolution medium 34, and the amount of the hyperpolarized sample 12. It depends on these characteristics. The standoff distance 62 can also be determined in part by the nozzle diameter 58. The exact fluid flow characteristics / ratio and the desired standoff will depend at least in part on these factors.

  The nozzle 56 itself can be attached to the first end 42 of the inner tube 36 in several ways. One method of placing the nozzle 56 at the output end 42 of the inner tube 36 includes placing another individual nozzle component on the inner tube 36. The nozzle 56 is disposed on the inner tube 36 prior to insertion of the outer tube 44 and the inner tube 36 in the vial 28. The nozzle 56 can also be formed on the output end 42 of the inner tube 36 from an inner tube material made of a moldable polymeric material. That is, the nozzle 56 can be formed by heating the inner tube polymer material to a flowing temperature. A needle (not shown) having the same outer diameter as the desired nozzle diameter 58 is inserted inside the inner tube 36 and the polymer material of the inner tube to be melted flows toward the needle. When it is possible to cool, a nozzle or orifice having a specific length and diameter is formed. The exact diameter 58 and depth 60 of the nozzle 56 can thus be measured by the configuration of the needle inserted into the inner tube 36 so that the nozzle 56 provides the desired fluid flow characteristics within the fluid path system 10. Can be formed.

  Referring again to FIG. 1, a container 66 containing an additional processing agent 68 is included in the fluid path system 10 to assist in the polarization of the sample 12. In one embodiment, container 66 contains gadolinium solution 68. Prior to sample 12 polarization, gadolinium solution 68 is injected down into the inner tube 36 and into the vial 28 to help and improve the hyperpolarization of the sample 12. That is, the gadolinium solution 68 is released from the container 66 through the syringe valve 40 configured as a three-way stool and the helium gas used to pressurize the container 66 before the sample 12 is cryogenized by the liquid helium bath 22. To be pushed into the inner tube 36. The gadolinium solution 68 is pushed down through the inner tube 36 by the helium gas pressure and enters the vial 28 to mix with the sample 12. The helium gas atmosphere present in the vial 28 covers the mixing of the gadolinium solution 68 and the pyruvate sample 12 so that proper mixing can occur. Any excess gas volume is pushed through a vent port present in the fluid pathway system 10, such as a vent port 70 in the holding container 48. Upon proper mixing of the gadolinium solution 68 and the sample 12, the prepared sample is brought to a cryogenic temperature by the liquid helium bath 22, as described above, and guided to a magnetic field for hyperpolarization. Inclusion of the container 66 within the fluid path system 10 is optional and is only necessary if the compound or material is added to the sample 12 prior to its polarization.

  Referring now to FIG. 3, another embodiment of the fluid pathway system 10 includes a dual syringe or injector 72, 74 that provides a lysis medium 34 to the system 10 for lysing the hyperpolarized sample 12. Yes. This two syringe arrangement can be implemented when a better pH adjustment than would otherwise be possible is needed due to the need to adjust the pH, filtration, or stability of the sample 12, for example. The dissolution medium 34 is broken down into two parts, one part containing an aqueous solution of the base 76 necessary to neutralize the pyruvic acid of the sample 12. The second portion of the dissolution medium 34 comprises an aqueous solution of buffer salt 78 (eg, TRIS). The two dissolution medium components 76, 78 are disposed in two motorized or pneumatic syringes 72, 74, both connected to the inner tube 36 of the fluid path system 10. At least one of base 76 and buffer salt 78 is heated to a suitable temperature to allow melting and lysis of frozen hyperpolarized sample 12. When the dissolution process begins, both syringes 72, 74 disperse their contents within the inner tube 36. The dispersion of base 76 and aqueous buffer salt 78 by double syringes 72, 74 is electronically controlled to adjust the concentration of base 76 in dissolution medium 34. That is, the amount of base 76 injected into the inner tube 36 to mix with the buffer salt 78 is adjusted so that the base 76 is continuously matched to the dissolved pyruvate stoichiometry of the sample 12. The When the hyperpolarized sample 12 is completely dissolved, only the syringe 74 containing the aqueous buffer salt solution continues to disperse the fluid within the inner tube 36. The aqueous buffer salt 78 then propels the bolus (ie, hyperpolarized solution) through the outer tube 44 and the filter 54 and into the holding container 48.

  As shown in FIG. 4, in one embodiment of flask 55, the flask includes a rubber septum 80 fitted over its inlet port. A spike 82 made of a non-metallic material is fitted to the second end 50 of the outer tube 44 and is configured to transmit the hyperpolarized solution from the outer tube 44 to the flask 55 through the septum 80. The The hyperpolarized solution is pushed from the outer tube 44 through the spike 82 and into the flask 55. The spike 82 can easily and quickly remove the flask 55 from the fluid path system 10 when a desired amount of hyperpolarized solution has been transferred into the flask 55.

  As shown in FIG. 5, the spike 82 comprises an elliptical needle 84 having a larger diameter 86 of 3.0 mm along one axis and a smaller diameter 88 of 0.3 mm along another axis. ing. Referring again to FIG. 4, an elliptically designed needle 84 having a thickness of, for example, about 32 mm with many of the cut incisions opposite the circular needle penetrates the septum 80 and thereby therein Reduce the force on septum 80 and needle 84 during insertion. Although having an oval design with a small diameter along one axis, the stiffness of the needle 84 is such that it provides strength to withstand the forces applied thereon during insertion through the septum 80. Further, the needle 84 is dimensioned so as not to adversely affect the flow rate of the hyperpolarized solution between the outer tube 44 and the flask 55.

  Also, there is a vertical spacing along the length of the needle 84 to form a fluid path 90 (shown in FIG. 5) and a fluid connection between the outer tube 44 and the flask 55 within the needle 84 of the spike 82. A fluid path hole 92 positioned in place is included. The fluid path hole 92 is designed to act as a spray nozzle / jet that diffuses the hyperpolarized solution as the solution is pushed through the hole 92. The diffusion of the fluid path holes 92 improves the homogenization of the hyperpolarized solution when a larger portion of the solution is pushed in different directions. Diffusion also allows for a higher surface area solution to be exposed, allowing the hyperpolarized solution temperature to drop before being injected into the patient.

  Although the fluid pathway system 10 described above includes an inner tube 36 and an outer tube 44 as shown in FIG. 1, it is contemplated that other configurations may be implemented. Referring now to FIG. 6, the fluid path system 10 is configured to have a dissolved fluid path 36 and a delivery fluid path 44 positioned in a parallel configuration. The dissolution fluid path is in fluid communication with the vial 28 to carry the dissolution medium from the syringe 32 and into the vial to dissolve the sample 12. The carrying fluid path is sealed to the vial 28 to carry the mixture of the dissolution medium 34 and the dissolved sample 12 from the vial in the form of a hyperpolarized solution that is carried to the flask 55 as needed.

  Thus, according to one embodiment of the invention, the fluid pathway system is attached to a vial with a frozen formulation therein, an output end in fluid communication with the vial and a pressure vessel containing a dissolution medium. A dissolution fluid path having an input end; and a delivery fluid path having a first end that is airtightly attached to the vial to transport a mixture of dissolved formulation and dissolution medium therefrom. The fluid path system also includes a holding container coupled to the second end of the transport fluid path to receive the mixture, and a dissolution positioned between the pressure container and the dissolution fluid path to control the flow of the dissolution medium. A fluid path valve and a transport fluid path valve for controlling the flow of the mixture from the transport fluid path to the holding vessel.

  According to another embodiment of the present invention, a polariser system for polarizing materials used in magnetic resonance (MR) imaging creates a magnetic field and a cryogenic cooling system that cools materials that are hyperpolarized to ultra-low temperatures. And a superconducting magnet positioned around the cryogenic cooling system to hyperpolarize the. The polariser system also includes a fluid delivery system that dissolves and carries the hyperpolarized material. The fluid delivery system further comprises a sample container having a material to be hyperpolarized therein, a syringe having a dissolution medium therein, and an inner tube coupled to the syringe for receiving and transporting the dissolution medium therethrough. The inner tube is in fluid communication with a sample container having an internal volume in which the dissolution medium and the hyperpolarized material are in fluid contact. The fluid delivery system also includes an outer tube that is hermetically coupled to the sample container to carry the hyperpolarized solution from the sample container consisting of the dissolution medium and the dissolved hyperpolarized material.

  According to yet another embodiment of the present invention, a method of manufacturing a fluid path system hermetically seals a first end of an outer tube against a vial with a solid material that is hyperpolarized therein. And positioning the inner tube within the outer tube, the inner tube having an output end in fluid communication with the interior volume of the vial. The method also includes connecting a syringe having a dissolution medium therein to the input end of the inner tube and connecting a holding container to the second end of the outer tube to receive the hyperpolarized solution therein. The hyperpolarized solution comprises a dissolution medium and a dissolved hyperpolarized material.

  While the invention has been described with reference to preferred embodiments, it will be appreciated that equivalents, alternatives, and modifications other than those explicitly described are possible and are within the scope of the appended claims. Further, the reference numerals in the claims corresponding to the reference numerals in the drawings are merely used for easier understanding of the present invention, and are not intended to narrow the scope of the present invention. Absent. The matters described in the claims of the present application are incorporated into the specification and become a part of the description items of the specification.

1 is a schematic block diagram of a fluid path system according to an embodiment of the present invention. It is sectional drawing of the liquid medicine bottle by one Embodiment of this invention. 2 is a schematic illustration of a portion of a fluid pathway system according to another embodiment of the invention. 2 is a cross-sectional view of a flask and spike according to one embodiment of the present invention. FIG. FIG. 5 is a cross-sectional view taken along 5-5 in FIG. 4. 2 is a schematic illustration of a portion of a fluid pathway system according to another embodiment of the invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Fluid pathway system 12 Formulation / sample 14 Hyperpolarizing device 16 Vacuum chamber 18 Cryogenic cooling system 20 Superconducting magnet 22 Liquid helium tank 24 Container 26 Sliding seal 28 Pill bottle 30 Pill bottle 30 Pressure vessel / syringe 34 Dissolution Medium 36 Dissolving fluid path 38 Input end 40 Dissolving fluid path valve 42 Output end 44 Transporting fluid path 46 First end 48 Holding container 50 Second end 52 Transporting fluid path valve 54 Filter cartridge 55 Receiving container 56 Nozzle 57 Heat exchanger 58 Nozzle diameter 59 Aseptic filter 60 Nozzle depth 62 Selected distance 64 Sample surface 66 Container 68 Treatment agent 70 Aeration port 72 Syringe 74 Syringe 76 Base 78 Buffer salt 80 Septum 82 Spike 84 From elliptical needle 86 Larger diameter less than 88 Diameter 90 Fluid path 92 Fluid path hole

Claims (9)

A fluid path system (10) comprising:
A vial (28) containing a formulation of hyperpolarized material (12) therein ;
A dissolution fluid path (36) having an output end (42) in fluid communication with the vial (28) and an input end (38) attached to a pressure vessel (32) containing a dissolution medium (34); ,
A delivery fluid path (44) having a first end (46) hermetically attached to the vial (28) to transport a mixture of dissolved formulation (12) and dissolution medium (34) therefrom. And
The dissolution fluid path (36) and the transport fluid path (44) are composed of tubes, the dissolution fluid path (36) is located inside or parallel to the transport fluid path (44),
The fluid path system (10) further comprises:
A receiving container (55) coupled to the second end (50) of the carrier fluid path (44) to receive the mixture;
A dissolution fluid path valve (40) positioned between the pressure vessel (32) and the dissolution fluid path (36) to control the flow of the dissolution medium (34);
A transport fluid path valve (52) for controlling the flow of the pre-mixture from the transport fluid path (44) to the receiving vessel (55);
A filter cartridge (54) included in the transport fluid path (44) for removing an electron paramagnetic agent (EPA) from the hyperpolarized solution before entering the receiving vessel (55);
The pressure vessel (32) and the cryogenically cooled chamber (18) containing the vial (28) therein, so as to seal the contents of the vial without contacting the atmospheric environment; A fluid path system (10), comprising a sliding sealing unit (26) positioned between said vials (28). A nozzle (56) attached to the output end (42) of the dissolution fluid path (36) is further provided to change the fluid flow of the dissolution medium (34) into the vial (28). A fluid path system (10) according to claim 1. The nozzle (56) includes a configuration of the dissolution medium (34) applied to the dissolution fluid path (36), a temperature of the dissolution medium (34) applied to the dissolution fluid path (36), and a dissolution fluid path ( Nozzle diameter (58) and nozzle depth (60) based on at least one of the pressure of the dissolution medium (34) applied to 36) and the amount of the formulation (12) applied to the vial (28). The fluid path system (10) according to claim 2, comprising: A fluid path system (10) according to any preceding claim, wherein the pressure vessel (32) is a syringe (32). The fluid path system (10) according to any one of the preceding claims, wherein the dissolved fluid path (36) is formed from a material having a different thermal conductivity than the conveying fluid path (44). The hyperpolarized material of the formulation (12) is a material for improving the contrast in at least one of a magnetic resonance (MR) imaging and nuclear magnetic resonance (NMR) spectroscopy, one of claims 1 to 5 The fluid path system (10) of claim 1. The fluid path system (10) according to any one of the preceding claims, wherein the dissolution medium (34) comprises a base solvent and a buffer in the pressure vessel. The vial (28), the dissolution fluid path (36), the transport fluid path (44), and the receiving container (55) are each sterile medical grade material so as to form a sterile environment for the mixture. The fluid path system (10) according to any one of the preceding claims, comprising: The fluid path system (10) according to any one of the preceding claims, wherein the sliding sealing unit (26) is configured to be slidable along the fluid path system (10).

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